Water-soluble, biocompatible polymers are of interest for possible biomedical applications such as formation of hydrogels for use as membranes, structural materials, or matrices for the immobilizaton of bioactive agents.
In U. S. Pat. No. 3,893,980 and in Macromolecules, 1977. Vol. 10, No. 4, pages 824-830, H. R. Allcock et al. describe the synthesis of phosphazene high polymers with glycino ethyl ester, alanino methyl ester, leucino methyl ester, and phenylalanino methyl ester substituents by the interaction of poly(dichlorophosphazene) with amino acid esters. Total halogen replacement was achieved only with glycine ethyl ester. Replacement of the remaining chlorine could be effected by the subsequent introduction of methylamino groups as cosubstituents. The objective of this work was to determine whether the polymers could be biocompatible as solids or biodegradable to harmless hydrolysis products. If the products proved to be soluble in aqueous media, they could possibly be used as plasma extenders or carrier molecules for chemotherapeutic drugs. As pointed out in the patent, the methylamino groups were utilized in order to impart hydrophilicity to the polymers, a feature which was deemed by the patentees to be very important.
In Journal of Controlled Release, 1986, Vol. 3, pages 143-154, C. W. J. Grolleman et al. describe the synthesis of bioerodable phosphazene polymers containing a model drug (phenylacetic acid) or a drug (naproxen) covalently bound to the chain through a spacer, L-lysine. Residual chlorine on the partially substituted polyphosphazene was replaced by reaction with glycine ethyl ester. Subsequent papers by Grolleman et al. (Ibid., 1986, Vol. 4 pages 119-131; and pages 133-142) describe experiments in vitro and in vivo using such naproxen-substituted polyphosphazene drug release systems.
J. Heller, U.S. Pat. No. 4,639,366, describes a controlled release device comprising (a) a polymer with at least one labile backbone bond per repeat unit and at least one pendant acid functionality per thousand repeat units, and (b) a therapeutic or biologically active agent incorporated within or prepared by reacting a polyol, preferably a diol, having a pendant acidic group with a polymer containing a labile backbone bond. Polymers mentioned for use in this reaction are polyorthoesters (including polyorthocarbonates), polyacetals, polyketals, polyesters and polyphosphazenes.
In Macromolecules, 1988, Vol. 21, No. 7, pp. 1980-1985, and in references cited therein, H. R. Allcock et al. describe the synthesis of certain poly(organophosphazenes) which are soluble in water and can be cross-linked to form membranes or hydrogels. The sodium salts of di(hydroxy-protected)glycerols reacted with poly(dichlorophosphazene) to produce polyphosphazenes bearing protected glyceryl side groups; subsequent deprotection yielded poly(diglycerylphosphazene) which was water soluble and cross-linkable. Interest is drawn toward these polymers (1) because the overall molecular structure of the polymer might allow hydrolytic breakdown to biologically innocuous products, and (2) because the presence of hydroxyl groups in the side units is expected (a) to generate water solubility, (b) to provide possible sites for cross-linking, and (c) to provide possible sites for the attachment of bioactive agents.
The present inventors, in prior co-pending Applications (Ser. No. 298,921, Ser. No. 298,922, Ser. No. 299,085 and 300,138, all filed Jan. 23, 1989) have disclosed novel substituted polyphosphazenes useful in the production of bioerodable devices.